rs72549310
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000110.4(DPYD):c.61C>T(p.Arg21*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000931 in 1,611,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000110.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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DPYD | ENST00000370192.8 | c.61C>T | p.Arg21* | stop_gained | Exon 2 of 23 | 1 | NM_000110.4 | ENSP00000359211.3 | ||
DPYD | ENST00000306031.5 | c.61C>T | p.Arg21* | stop_gained | Exon 2 of 6 | 1 | ENSP00000307107.5 | |||
DPYD | ENST00000460019.1 | n.136C>T | non_coding_transcript_exon_variant | Exon 2 of 3 | 2 | |||||
DPYD | ENST00000646851.1 | n.710C>T | non_coding_transcript_exon_variant | Exon 6 of 6 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152004Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250890Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135594
GnomAD4 exome AF: 0.00000959 AC: 14AN: 1459292Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10AN XY: 726088
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152122Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74364
ClinVar
Submissions by phenotype
Dihydropyrimidine dehydrogenase deficiency Pathogenic:5
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Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as a Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with dihydropyrimidine dehydrogenase deficiency and 5-fluorouracil toxicity (MIM#274270). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 11783493). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (3 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. It has been previously reported in patients with dihydropyrimidine dehydrogenase deficiency and 5-fluorouracil toxicity (ClinVar, PMID: 12562666). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional analysis shows that this variant resulted in an absence of detectable dihydropyrimidine dehydrogenase activity (PMID: 24648345). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
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not provided Pathogenic:1
Reported with a second DPYD variant in a patient with severe 5-fluorouracil toxicity (van Kuilenburg et al., 2003); Published functional studies demonstrate a damaging effect on DPD enzyme activity, reducing it to less than 12.5% activity relative to wild type DPD (Offer et al., 2014); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 25381393, 25502898, 24648345, 17121937, 33305610, 26621101, 21833589, 32707991, 34621706, 19287123, 23199091, 35314707, 12562666) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at